More deaths each year are attributable to nicotine dependence than to all illicit drug abuse combined. The causes and mechanisms of this disorder include social, physiological and cognitive components. While it is doubtful that effects on cognition are the primary reason for cigarette smoking, self-reports of why people smoke indicate that these effects are significant contributors. The broad objective of this work is to elucidate the neural circuitry involved in the cognitive effects of smoking and withdrawal. We will test how the activity of prefrontal brain regions that mediate cognitive control differs in nicotine abstinence and satiety. Cognitive control refers to brain functions that guide voluntary, complex actions. We also will test how patterns of brain activity related to cognitive performance differ in smokers and nonsmokers. Our long-term objectives are to provide information on how nicotine and smoking affect brain circuitry important to cognitive functions, and how these functions may differ in smokers and nonsmokers (either as effects of smoking or as etiological factors in nicotine dependence). Prior and ongoing studies have indicated that abstinence from smoking, nicotine administration, and even a history of smoking can affect performance on tests of cognitive control. Brain imaging studies with these tasks show activation of the dorsolateral prefrontal cortex (DLPFC) and the anterior cingulate cortex (ACC) as well as other brain regions. One such task is the Stroop Color-Word Interference Task, which requires focused attention and response inhibition while conflicting stimuli are presented. Performance of this task reliably activates ACC. Another test of cognitive control that shows possible effects of smoking is the N-Back Task, which requires working memory and generally produces activation of DLPFC. We will use functional magnetic resonance imaging (fMRI) to measure brain activation during performance of these two well-studied tasks. Our measure of regional activation in the brain will be change in magnetic resonance signal, representing relative hemodynamic change. We have two primary objectives. Our first specific aim is to determine the effects of smoking history and abstinence on brain function during performance of the N-Back Task and the Stroop Task. Smokers and nonsmokers will be tested with fMRI and cognitive activation. The smokers will be tested both in a state of satiety (after smoking ad libitum) as well as after 15-17 h of abstinence. Our second aim is to determine if smoking will reverse differences in brain activation and/or improve performance on the N-Back and Stroop tasks. Following each initial cognitive activation test session, both at satiety (after smoking ad libitum) and during abstinence, smokers will be allowed to smoke (ad libitum for 10 min) and will be re-tested. Nonsmokers, serving as controls, will be re-tested at corresponding times.